Neurophysiology has been a subject of study since as early as 4,000 B.C.

In the early B.C. years, most studies were of different natural sedatives like alcohol and poppy plants. In 1700 B.C., the Edwin Smith surgical papyrus was written. This papyrus was crucial in understanding how the ancient Egyptians understood the nervous system. This papyrus looked at different case studies about injuries to different parts of the body, most notably the head. Beginning around 460 B.C., Hippocrates began to study epilepsy, and theorized that it had its origins in the brain. Hippocrates also theorized that the brain was involved in sensation, and that it was where intelligence was derived from. Hippocrates, as well as most ancient Greeks, believed that relaxation and a stress free environment was crucial in helping treat neurological disorders. In 280 B.C., Erasistratus of Chios theorized that there were divisions in the vestibular processing the brain, as well as deducing from observation that sensation was located there.

In 177 Galen theorized that human thought occurred in the brain, as opposed to the heart as Aristotle had theorized. The optic chiasm, which is crucial to the visual system, was discovered around 100 C.E. by Marinus. Circa 1000, Al-Zahrawi, living in Spain, began to write about different surgical treatments for neurological disorders. In 1216, the first anatomy textbook in Europe, which included a description of the brain, was written by Mondino de’Luzzi. In 1402, St Mary of Bethlehem Hospital (later known as Bedlam in Britain) was the first hospital used exclusively for the mentally ill.

In 1504, Leonardo da Vinci continued his study of the human body with a wax cast of the human ventricle system. In 1536, Nicolo Massa described the effects of different diseases, such as syphilis on the nervous system. He also noticed that the ventricular cavities were filled with cerebrospinal fluid. In 1542, the term physiology was used for the first time by a French physician named Jean Fernal, to explain bodily function in relation to the brain. In 1543, Andreas Vesalius wrote On the Workings of the Human Body, which revolutionized the study of anatomy. In this book, he described the pineal gland and what he believed the function was, and was able to draw the corpus striatum which is made up of the basal ganglia and the internal capsule. In 1549, Jason Pratensis published De Cerebri Morbis. This book was devoted to neurological diseases, and discussed symptoms, as well as ideas from Galen and other Greek, Roman and Arabic authors. It also looked into the anatomy and specific functions of different areas. In 1550, Andreas Vesalius worked on a case of hydrocephalus, or fluid filling the brain. In the same year, Bartolomeo Eustachio studied the optic nerves, mainly focusing on their origins in the brain. In 1564, Giulio Cesare Aranzio discovered the hippocampus, naming it such due to its shape resemblance to a sea horse.